Purpose: In previous cancer vaccine clinical trials targeting survivin, induction of specific CD8 + T-cell responses did not consistently lead to clinical responses. Considering the critical role of CD4 + T-cell help in generating antitumor immunity, integration of anti-survivin CD4 + T-cell responses may enhance the efficacy of anti-survivin cancer immunotherapy. Human leukocyte antigen (HLA)-DP4 is emerging as an attractive MHC target allele of CD4 + T cell-mediated immunotherapy, because it is one of the most frequent HLA alleles in many ethnic groups. In this article, we aimed to elucidate DP4-restricted CD4 +T-cell responses against survivin in cancer patients. Experimental Design: We generated a human cell-based artificial antigen-presenting cell (aAPC) expressing HLA-DP4, CD80, and CD83 and induced DP4-restricted antigen-specific CD4 + T cells. The number, phenotype, effector function, and in vitro longevity of generated CD4 + T cells were determined. Results: We first determined previously unknown DP4-restricted CD4 + T-cell epitopes derived from cytomegalovirus pp65, to which sustained Th1-biased recall responses were induced in vitro by using DP4-aAPC. In contrast, DP4-aAPC induced in vitro both Th1 and Th2 long-lived anti-survivin CD4 + T cells from cancer patients. Both survivin-specific Th1 and Th2 cells were able to recognize survivin-expressing tumors in a DP4-restricted manner. Neither survivin-specific interleukin 10 secreting Tr1 cells nor Th17 cells were induced by DP4-aAPC. Conclusions: DP4-restricted anti-survivin Th1 and Th2 immunity with sufficient functional avidity can be induced from cancer patients. The development of strategies to concurrently induce both CD4 +and CD8 + T-cell responses against survivin is warranted for optimal anti-survivin cancer immunotherapy.
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